Leptin, a peptide hormone secreted by adipocytes, is a major regulator of energy and glucose metabolism. Leptin deficiency causes obesity and diabetes, whereas leptin overexpression in animal models decreases body fat and enhances glucose metabolism. Because most forms of human obesity are associated with leptin resistance, key questions regarding leptin are: What regulates leptin resistance and sensitivity? And does increasing leptin sensitivity protect against obesity and diabetes? Studies of mice lacking acyI:CoA diacylglycerol acyltransferase (DGAT) may address these questions. DGAT catalyzes the final step in the major pathways of triglyceride synthesis. DGAT-deficient (Dgat-/-) mice, despite decreased plasma leptin concentrations, have reduced body fat, increased energy expenditure, and enhanced glucose disposal, findings that are similar to those in rodents with leptin overexpression. Moreover, Dgat-/- mice have increased weight loss in response to leptin infusion. These results are consistent with the hypothesis that Dgat-/- mice have increased leptin sensitivity. Determining how DGAT deficiency increases leptin sensitivity will be the subject of this research proposal. The Specific Aims are: (1) to determine whether DGAT deficiency increases leptin sensitivity through a central or peripheral mechanism, and (2) to determine the tissue(s) in which DGAT deficiency increases leptin sensitivity. For Specific Aim 1, the expression and activation of functional leptin receptors will be measured in both the hypothalamus and selected peripheral tissues of Dgat-/- and wild-type mice. For Specific Aim 2, transgenic mice that overexpress DGAT in selected tissues will be generated. These transgenic mice will then be crossed with Dgat-/- mice for complementation studies to determine if restoring DGAT expression in a specific tissue reverses the increased leptin sensitivity in Dgat-/- mice.